Human noroviruses in the Caliciviridae family are the major cause of non-bacterial epidemic gastroenteritis worldwide. Primary human norovirus infection does not elicit lasting protective immunity, a fact that could greatly affect the efficacy of vaccination strategies. Our long term goal is to elucidate the mechanisms by which noroviruses avoid the induction of protective immunity, ultimately translating this knowledge into successful vaccination approaches. Little is known regarding the pathogenesis of human noroviruses or the immune responses that control them because there has previously been no small animal model or cell culture system of infection. Data from our laboratory has defined the first small animal model of norovirus infection: We discovered the first murine norovirus (MNV), MNV-1, and demonstrated its cultivation in macrophages and dendritic cells in vitro. We have now used these unique models to examine norovirus pathogenesis and immunity. We have determined that MNV-1 is infectious orally and is associated with the induction of gastroenteritis in multiple immunocompetent mouse strains, confirming the utility of this virus as a model to study human norovirus pathogenesis. Importantly, we have also determined that primary MNV-1 infection fails to afford protection to re-challenge with homologous virus. Thus, MNV-1 represents a valuable model with which to dissect the pathophysiological basis for the lack of lasting protection to human norovirus infection. Interestingly, murine and human noroviruses appear to persistently infect their hosts. For murine noroviruses, persistent virus can be detected in immune-inductive sites including the mesenteric lymph nodes and the spleen. Our specific hypothesis is that persistent norovirus infection of immune- inductive sites, and specifically of antigen presenting cells within these sites, impairs the development of protective immunity. We have now determined that the magnitude of memory immune responses elicited by primary MNV-1 infection inversely correlates with inoculum dose. Thus, to test our hypothesis, we will (i) determine whether there is a direct correlation between persistent MNV-1 infection and inoculum dose;(ii) characterize the effect of inoculum dose on mucosal memory immune responses to primary MNV-1 infection;and (iii) determine whether dendritic cells and macrophages in immune-inductive sites are persistently infected with MNV-1. Our ultimate goal is to understand how noroviruses impair the functioning of antigen presenting cells such that protective norovirus immunity is not elicited and/or maintained, and to translate this information into effective vaccine design. PUBLIC HEALTH RELEVANCE: Human noroviruses in the Caliciviridae family are the major cause of non-bacterial epidemic gastroenteritis worldwide but infection does not induce lasting protection. Our long term goal is to elucidate the mechanisms by which norovirus infection avoids the induction of protective immunity, ultimately translating this knowledge into successful vaccination strategies. Our specific hypothesis is that persistent norovirus infection of immune cells inhibits the development of protective immunity.